1. Field of the Invention
The present invention relates to a novel stabilized superoxide dismutase, hereinafter referred to as "stabilized SOD" or "modified SOD", for use as an active ingredient of medicines such as anti-inflammatory agents, ischemic disease treating agents, cardiac infarction treating agents, radial ray lesion treating agents, tumor metastasis-preventing agents and stroke treating agents.
2. Description of the Prior Art
Superoxide dismutase, hereinafter referred to as "SOD", can be employed as the medicines mentioned above, since it can remove toxic substances derived from oxygen, in a living body.
However, when SOD is administered in the living body by intravenous injection, the half life of the SOD in the blood circulation is only a few minutes. Therefore the administered SOD is rapidly lost from the circulation in the living body. Accordingly, the enzymatic activity of the SOD cannot be retained for a time sufficient to remove toxic substances to a sufficient extent. Moreover, it causes adverse reactions by the over administration of SOD to the living body.
In order to resolve the problems mentioned above, many chemical modifications of SOD have been performed in order to extend the life of SOD in the circulation of the living body. The half life time (T-50) of chemically modified SOD in the circulation varies dependent upon the molecular weight of the modified SOD, and therefore modified SOD having a high molecular weight is expected to have a greater half survival time (see (1) E. Boccu, G. P. Velo, F. M. Veronese, Pharmacol., Res. Commun., 14, 113, 1982; (2) E. Boccu, R. Largajolli, F. M. Veronese, Z. Naturforschung, 38, 94, 1983; and (3) Pyatak et al, Res. Commun. Chem. Pathol. Pharm. 29, 113, 1980).
In these cases, a large number of poly(alkylene oxide) molecules of which one terminal group is protected with a methoxy group, are chemically attached to one SOD molecule through the other terminal group of the poly(alkylene oxide) to obtain a high molecule weight SOD derivative).
The method used for the modification of SOD with Ficoll, rat albumin and with poly(ethylene oxide) by P. S. Pyatak et al, is not good enough to be employed for medical uses because the SOD activity is as low as 50% of the original enzyme.
On the other hand, in the method for modification with methoxypolyethylene glycol as described by Boccu et al (see references (1) and (2) above), it is not possible to obtain a product having an enzyme activity sufficiently high for medical purposes and having a long half survival time in the blood circulation.